Cariprazine in Bipolar Disorder: Clinical Efficacy ...

Adv Ther (2013) 30(2):102�C13.

DOI 10.1007/s12325-013-0004-9

REVIEW

Cariprazine in Bipolar Disorder: Clinical Efficacy,

Tolerability, and Place in Therapy

Leslie Citrome

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Received: December 13, 2012 / Published online: January 28, 2013

? Springer Healthcare 2013

ABSTRACT

Cariprazine is a dopamine D3-preferring

D3/D2 receptor partial agonist in late-stage clinical

development for the treatment of bipolar disorder

(manic/mixed and depressive episodes), as well as

for schizophrenia, and as an adjunctive agent for

the treatment of major depressive disorder. Three

phase 2 or 3, 3-week, randomized controlled trials

in bipolar mania or mixed episodes have been

completed and reported as poster presentations or

in press releases by the manufacturer. Superiority

over placebo on the Young Mania Rating Scale

total score was evidenced for daily doses

of cariprazine 3�C12 mg/day. In short-term

randomized controlled trials, cariprazine does not

L. Citrome (*)

Clinical Professor of Psychiatry & Behavioral Sciences,

New York Medical College, Valhalla, New York, USA

11 Medical Park Drive, Suite 106, Pomona,

NY 10970, USA

e-mail: citrome@

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appear to adversely impact metabolic variables,

prolactin, or the electrocardiogram (ECG) QT

interval. The most commonly encountered

adverse events in the mania trials were

extrapyramidal disorder, akathisia, insomnia,

vomiting, restlessness, sedation, vision blurred,

and pain in extremity in the phase 2 trial where

this was presented in a poster, and akathisia,

extrapyramidal disorder, tremor, dyspepsia,

vomiting, dizziness, diarrhea, somnolence,

restlessness, and pyrexia for the phase 3 trial

where this was presented in a poster. With the

exception of akathisia and extrapyramidal

disorder, the differences in incidence versus

placebo for these events were generally small. If

approved by regulatory authorities, cariprazine

would join aripiprazole as the second dopamine

receptor partial agonist antipsychotic available

for clinical use in persons with bipolar mania

or mixed episodes. Cariprazine differs from

aripiprazole in terms of dopamine D3 receptor

selectivity. Further studies would be helpful to

discern the distinguishing features of cariprazine

from other antimanic agents.

Keywords: Antipsychotic; Bipolar disorder;

Cariprazine; Depression; Dosing; Efficacy;

Mania; Manic/mixed; Tolerability

Adv Ther (2013) 30(2):102�C13.

INTRODUCTION

Although there are several agents that have received

regulatory approval for the treatment of bipolar

disorder, it is often difficult to select the treatment(s)

that will result in sufficient reduction in symptoms

together with reasonable tolerability and safety.

Moreover, although most available treatments are

approved for the treatment of acute mania, fewer

are approved for both manic and mixed episodes,

fewer still for maintenance treatment, and only two

for the treatment of acute bipolar depression [1, 2].

The agents themselves vary greatly in terms of ease

of use and tolerability [1, 2].

Cariprazine is a new second-generation

antipsychotic, in the late-stage of clinical

development for the treatment of bipolar disorder

(manic/mixed and depressive episodes), as well as

for schizophrenia and as an adjunctive agent for

the treatment of major depressive disorder. The

intent of this review is to describe the efficacy,

tolerability, and potential place in therapy of

cariprazine for the treatment of bipolar disorder. A

PubMed search was conducted on October 31 2012

using the search terms ��cariprazine,�� ��RGH-188,��

and ��RGH 188�� without any date or language

restrictions. The resulting 15 publications and their

reference lists were then specifically examined for

primary sources of information with emphasis

on the use of cariprazine in persons with bipolar

disorder. A query of the website

on October 31 2012 yielded 18 separate records

and provided additional information regarding

registered trials of cariprazine. The abstract books

for the annual scientific meetings of the American

Psychiatric Association (2008�C2012) [3�C7], Institute

on Psychiatric Services of the American Psychiatric

Association (2008�C2012) [8�C12], New Clinical

Drug Evaluation Unit (2008�C2012) [13�C17], and

American College of Neuropsychopharmacology

(2008�C2011) [18�C21], were also examined and

yielded additional relevant data that have not

103

yet been published as full reports in peer-refereed

journals. Whenever possible, reproductions of the

poster presentations were obtained in digital PDF

format from the authors. Press releases from the

manufacturer were also reviewed for preliminary

clinical trial results that have not yet been

presented at scientific meetings. A similar search

strategy has been used by the author in other

reviews of cariprazine, including a companion

review regarding cariprazine for the treatment of

schizophrenia [22], and a systematic review with

emphasis on the chemistry, pharmacodynamics,

and pharmacokinetics of cariprazine [23].

PHARMACODYNAMICS AND

PHARMACOKINETICS

The pharmacodynamics and pharmacokinetics

of cariprazine are reviewed in more detail

elsewhere [22, 23]. Cariprazine is a dopamine

D3-preferring D3/D2 receptor partial agonist [24].

The in vitro binding profile of cariprazine is

summarized in Table 1.

Table 1 In vitro binding affinities for cariprazine in human

receptors [24]

Receptor

Ki (nM) Comments

Dopamine D3

0.085

Partial agonist

Dopamine D2L

0.49

Partial agonist

Dopamine D2S

0.69

Partial agonist

Serotonin 5-HT2B

0.58

Antagonist

Serotonin 5-HT1A

3

Partial agonist

Serotonin 5-HT2A

19

Antagonist

Histamine H1

23

Antagonist

Serotonin 5-HT7

111

Antagonist

Serotonin 5-HT2C

134

Antagonist

Ki binding affinity

Lower values denotes higher affinity

Low affinity was observed for all tested adrenergic

receptors

104

Adv Ther (2013) 30(2):102�C13.

Although the pharmacokinetics of cariprazine

in subjects with bipolar disorder is not

known, the pharmacokinetics of cariprazine

was tested in small short-term studies in

both healthy volunteers and in subjects

with schizophrenia, with similar results [25].

Maximum concentration was observed in 3?4 h

under fasting conditions, with food causing

a slight delay but no significant effect on the

extent of absorption. The mean half-life for

cariprazine was 2�C5 days over a dose range of

1.5�C12.5 mg in the subjects with schizophrenia.

Cariprazine is metabolized by cytochrome

P450 3A4 (CYP3A4) and, to a lesser extent,

by cytochrome P450 2D6 (CYP2D6) [26].

There are two active metabolites of note,

desmethyl-cariprazine and didesmethylcariprazine. Didesmethyl-cariprazine��s half-life is

substantially longer than that for cariprazine and

systemic exposure to didesmethyl-cariprazine can

be several times higher than that for cariprazine.

SHORT-TERM CLINICAL TRIALS

Overview

Table 2 [27�C31] provides an overview of the

double-blind randomized efficacy trials of

cariprazine for bipolar disorder in adults, as

conducted by the manufacturer. Results from

one phase 2 (RGH-MD-31 [27]) and two phase 3

(RGH-MD-32 [28] and RGH-MD-33 [29]) shortterm, randomized controlled trials of cariprazine

in subjects with bipolar mania/mixed episodes

have been reported in posters at scientific

meetings [27, 28] and in a press release from

the manufacturer [29]. Results from a study

in bipolar depression have been reported in a

press release [30], and another study in bipolar

depression is in progress [31].

In the studies for bipolar mania/mixed

episodes, subjects could receive up to 3 weeks

of randomized treatment. The primary efficacy

Table 2 Summary of double-blind randomized efficacy trials of cariprazine for bipolar disorder in adults, as conducted by

the manufacturer

Length N

(weeks)

Cariprazine daily dose/ Active

dose ranges (N)

control

Placebo, Comments

N

RGH-MD-31 [27] 2

3

238

3.0�C12.0 mg (118)

None

120

Acute mania. Unpublished.

Presented as a poster.

RGH-MD-32 [28] 3

3

312

3.0�C12.0 mg (158)

None

154

Acute mania. Unpublished.

Presented as a poster.

RGH-MD-33 [29] 3

3

497

3.0�C6.0 mg (167),

6.0�C12.0 mg (169)

None

161

Acute mania. Unpublished.

Limited information is

available in a press release.

RGH-MD-52 [30] 2

8

233

0.25�C0.75 mg (ND),

1.5�C3.0 mg (ND)

None

ND

Bipolar depression.

Unpublished. Limited

information is available in a

press release.

RGH-MD-56 [31] 2

8

600

0.75 mg (NA),

1.5 mg (NA),

3.0 mg (NA)

None

NA

Ongoing study in bipolar

depression.

Study

Phase

NA not applicable, ND not disclosed

Adv Ther (2013) 30(2):102�C13.

Point change from baseline

0

105

RGH-MD-31 [27] RGH-MD-32 [28] RGH-MD-33 [29]

�C1

�C2

�C3

�C4

�C5

�C6

�C7

�C8

3.0�C12.0 mg

3.0�C6.0 mg

6.0�C12.0 mg

Fig. 1 Cariprazine efficacy outcomes: Young Mania Rating

Scale (YMRS) total score difference from placebo, by study

and daily dose, for three 3-week randomized controlled

trials. All cariprazine arms were statistically significantly

superior to placebo. In RGH-MD-31 [27], baseline YMRS

total score was 30.2 for placebo and 30.6 for cariprazine;

last observation carried forward (LOCF) change was �C7.2

for placebo and �C13.3 for cariprazine. In RGH-MD-32

[28], baseline YMRS total score was 32.1 for placebo

and 32.3 for cariprazine; mixed-effects model of repeated

measures (MMRM) change was displayed graphically

in the poster and was approximately �C15 for placebo

and approximately �C19 for cariprazine at day 21, and

the reported least squares mean difference (LSMD) was

reported as �C4.3. Limited information has been reported

regarding RGH-MD-33 [29]; the press release reports that

the LSMD obtained by MMRM at day 21 was �C6.1 for

cariprazine 3�C6 mg/day and �C5.9 points for cariprazine

6�C12 mg/day, relative to patients receiving placebo

measure was the Young Mania Rating Scale

(YMRS) total score; the primary outcome was

change from baseline on the YMRS total score at

the 3-week endpoint. Figure 1 [27�C29] provides

an overview of the YMRS total score difference

from placebo at endpoint for the three studies.

Table 3 [27, 28] provides an overview of the

outcomes of response and remission for the two

studies where this was reported. All cariprazine

treatment arms were statistically superior to

placebo on the primary outcome. There were no

active controls.

RGH-MD-31

This flexible-dose study was conducted

internationally, with approximately 60% of

the subjects enrolled at US sites [27]. Inclusion

criteria included a diagnosis of bipolar I disorder,

manic or mixed type, with or without psychotic

features, YMRS score of at least 20, with a score

of ��4 on at least two of four of the following

YMRS items: irritability, speech, content,

disruptive/aggressive behavior. Subjects were

18�C65 years of age. Excluded were persons with

rapid cycling, those in their first manic episode,

subjects considered a suicide risk, and subjects

with a Montgomery-Asberg Depression Rating

Scale (MADRS) score of ��18. After up to 4 days of

Table 3 Responder and remission rates and number needed to treat (NNT) versus placebo as reported from short-term,

randomized controlled trials of cariprazine for manic/mixed episodes of bipolar disorder

RGH-MD-31 [27]

RGH-MD-32 [28]

Cariprazine

3�C12 mg/day

(n = 118)

Placebo

(n = 117)

NNT

Cariprazine

3�C12 mg/day

(n = 158)

Placebo

(n = 152)

NNT

Responders

48%

25%

5

59%

44%

7

Remitters

42%

23%

6

52%

35%

6

Response is defined as a decrease in the Young Mania Rating Scale of at least 50% from baseline, last observation carried

forward (LOCF)

Remission is defined as a Young Mania Rating Scale total score no greater than 12 at LOCF endpoint

106

washout off medications in an inpatient setting,

238 subjects were randomized (safety population

included 236 subjects) to cariprazine or placebo.

Subjects randomized to cariprazine received

1.5 mg/day on day 1, and then titrated within

the range of 3�C12 mg/day based on response

and tolerability as judged by the investigator.

Hospitalization was mandatory during screening

and the first 2 weeks of double-blind treatment.

Discharge was possible on day 14 or after if the

Clinical Global Impressions Severity (CGI-S)

score was no greater than 3, the subject was

otherwise not at significant risk for suicide or

violent behavior, and was ready for discharge

in the opinion of the investigator. Mean age of

subjects ranged from 38 to 39 years across the two

treatment arms; male gender ranged from 65%

to 68%; white race ranged from 40% to 47%; and

baseline YMRS total score ranged from 30 to 31.

In total, 36�C38% of patients discontinued the

trial prematurely. Mean duration of treatment

was 17 days and the overall mean daily dose

was 8.8 mg/day. Cariprazine was statistically

significantly superior to placebo on the primary

efficacy parameter and on the CGI-S, Clinical

Global Impressions-Improvement (CGI-I), and

Positive and Negative Syndrome Scale (PANSS),

but not on the MADRS. Compared with placebo,

cariprazine-treated subjects had significantly

greater rates of YMRS response (at least 50%

reduction from baseline) and remission (total

score no greater than 12).

In an analysis of single items from the YMRS,

for each YMRS item cariprazine was statistically

significantly superior to placebo. Mean changes in

clinical laboratory values were small and similar

between the groups except for slightly higher

levels in liver enzymes for the cariprazine group.

Mean changes in blood pressure and pulse were

higher in the cariprazine group relative to placebo.

The incidence of orthostatic hypotension or ECG

changes was similar between cariprazine- and

Adv Ther (2013) 30(2):102�C13.

placebo-treated subjects. There was a higher

incidence of extrapyramidal-related symptoms

in the cariprazine group relative to placebo.

Treatment emergent adverse events with an

incidence at least 5% for any of the cariprazine

treatment arms and at least twice that for placebo

were extrapyramidal disorder, akathisia, insomnia,

vomiting, restlessness, sedation, vision blurred,

and pain in extremity. Differences from placebo

were generally small except for extrapyramidal

disorder and akathisia where the numbers needed

to harm (NNH) versus placebo were 7 and 8,

respectively (see Table 4a [27]).

RGH-MD-32

This flexible-dose study was conducted

internationally [28]. Inclusion criteria included

a diagnosis of bipolar I disorder, manic or mixed

type, with or without psychotic features, YMRS

score of ��20, with a score of ��4 on at least two

of four of the following YMRS items: irritability,

speech, content, disruptive/aggressive behavior.

Subjects were 18�C65 years of age. Excluded were

persons with rapid cycling, those in their first

manic episode, subjects considered a suicide

risk, and subjects with a MADRS score of ��18.

After up to 4�C7 days of washout off medications

in an inpatient setting, 312 subjects were

randomized to cariprazine or placebo. Subjects

randomized to cariprazine received 1.5 mg/day

on day 1. Starting on day 2, the dose could be

increased in increments of 3 mg to a maximum

of 12 mg/day by day 7, based on patient

response and tolerability. Hospitalization was

mandatory during screening and the first

2 weeks of double-blind treatment. Discharge

was possible on day 14 or after if the CGI-S

score was no greater than 3, the subject was

otherwise not at significant risk for suicide or

violent behavior, and was ready for discharge

in the opinion of the investigator. Mean age of

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